Hydrocarbon Oxidation Methods for Synthesis

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DESCRIPTION (provided by applicant): The primary focus of this proposal is the discovery and development of highly selective, catalytic allylic C-H functionalization reactions that can be broadly applied to synthesis. Using these reactions to develop strategies for effecting highly efficient syntheses of molecules with valuable properties is one of our ultimate objectives. Another key objective is the mechanistic study of such systems in order to elucidate new fundamental principles of catalyst design and chemical reactivity. We have recently discovered a new class of sulfoxide-based palladium allylic C-H oxidation catalysts that provide access to either linear (E)-allylic acetates or branched allylic acetates from a wide variety of terminal olefin substrates. The distinctive features of these allylic C-H oxidation systems is that they require no heteroatom directing functional group on the substrate to achieve high reactivity and regioselectivity and are extraordinarily functional group tolerant. This revised grant application details our plans to fully optimize, based upon preliminary findings, these two reactions for use in fine chemical synthesis. Towards this goal, we have new preliminary data that: 1. identifies conditions to effect catalytic enantioselective branched allylic oxidation, 2. supports the claim that the allylic C-H macrolactonization method we propose to develop will have broad scope, 3. suggests that other nucleophiles will be competent for allylic C-H functionalization. On the basis of these results, we propose the following: 1. detailed mechanistic studies to determine the nature of reactive intermediates in the two allylic oxidation systems and the effects of sulfoxide and BQ on their formation and reactivity; 2. development of the branched allylic oxidation reaction into an enantioselective process and macrolactonization method for widespread use in synthesis, 3. optimization and use of the linear allylic oxidation reaction to effect a highly streamlined route to the hexoses, 4. exploration of the Pd/sulfoxide reaction manifolds for effecting a broad range of allylic C-H functionalization reactions. The discovery and development of mild and selective C-H functionalization methods, like the ones described in this proposal, stands to impact significantly on both the rate and expense in which new drugs are discovered and manufactured.